PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a clinically-relevant rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury, while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion that is most relevant to the SCI clinical population, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function. HIGHLIGHTS: PTEN antagonist peptide promotes partial diaphragm function recovery in chronic cervical contusion SCI.PTPσ inhibitory peptide does not impact diaphragm function recovery in chronic cervical contusion SCI.PTEN antagonist peptide promotes growth of bulbospinal rVRG axons in chronic cervical contusion SCI.PTPσ peptide does not affect rVRG axon growth in chronic cervical contusion SCI.

Implementation of the Operating Room Black Box Research Program at the Ottawa Hospital Through Patient, Clinical, and Organizational Engagement: Case Study.

BACKGROUND: A large proportion of surgical patient harm is preventable; yet, our ability to systematically learn from these incidents and improve clinical practice remains limited. The Operating Room Black Box was developed to address the need for comprehensive assessments of clinical performance in the operating room. It captures synchronized audio, video, patient, and environmental clinical data in real time, which are subsequently analyzed by a combination of expert raters and software-based algorithms. Despite its significant potential to facilitate research and practice improvement, there are many potential implementation challenges at the institutional, clinician, and patient level. This paper summarizes our approach to implementation of the Operating Room Black Box at a large academic Canadian center. OBJECTIVE: We aimed to contribute to the development of evidence-based best practices for implementing innovative technology in the operating room for direct observation of the clinical performance by using the case of the Operating Room Black Box. Specifically, we outline the systematic approach to the Operating Room Black Box implementation undertaken at our center. METHODS: Our implementation approach included seeking support from hospital leadership; building frontline support and a team of champions among patients, nurses, anesthesiologists, and surgeons; accounting for stakeholder perceptions using theory-informed qualitative interviews; engaging patients; and documenting the implementation process, including barriers and facilitators, using the consolidated framework for implementation research. RESULTS: During the 12-month implementation period, we conducted 23 stakeholder engagement activities with over 200 participants. We recruited 10 clinician champions representing nursing, anesthesia, and surgery. We formally interviewed 15 patients and 17 perioperative clinicians and identified key themes to include in an information campaign run as part of the implementation process. Two patient partners were engaged and advised on communications as well as grant and protocol development. Many anticipated and unanticipated challenges were encountered at all levels. Implementation was ultimately successful, with the Operating Room Black Box installed in August 2018, and data collection beginning shortly thereafter. CONCLUSIONS: This paper represents the first step toward evidence-guided implementation of technologies for direct observation of performance for research and quality improvement in surgery. With technology increasingly being used in health care settings, the health care community should aim to optimize implementation processes in the best interest of health care professionals and patients.

Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong chinese patients.

INTRODUCTION: Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well characterized. METHODS: This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan's criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression. RESULTS: A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value: .01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value: .007). CONCLUSION: The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese.

Incidence, Presentation, and Risk Factors for Sodium Valproate-Associated Hyperammonemia in Neurosurgical Patients: A Prospective, Observational Study.

OBJECTIVE: Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS: This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS: In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 µmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 µmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS: Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.

The importance of aspirin, catheterization accuracy, and catheter design in external ventricular drainage-related hemorrhage: a multicenter study of 1002 procedures.

BACKGROUND: External ventricular drainage (EVD) is the commonest neurosurgical procedure performed in daily neurosurgical practice, but relatively few studies have investigated the incidence and risk factors of its related hemorrhagic complications. METHODS: This was a multicenter retrospective review of consecutive EVD procedures. Patients 18 years or older who underwent EVD and had a routine postoperative computed tomography (CT) scan performed within 24 hours were included. EVD-related hemorrhage was defined as new intracranial hemorrhage immediately adjacent or within the ventricular catheter trajectory. The volume of hemorrhage and the position of the catheter tip were assessed. A review of patient-, disease-, and surgery-related factors including the ventricular catheter design utilized was conducted. The Bonferroni correction was applied to the alpha level of significance (0.05) for multivariable analysis. RESULTS: Nine hundred sixty-two patients underwent 1002 EVD performed by neurosurgeons in the operating theater. Sixteen percent (154) of patients were on aspirin before the procedure. Thirty-four percent (333) of patients had intracerebral hemorrhage, 25% (251) had aneurysmal subarachnoid hemorrhage and 16% (158) had traumatic brain injury. The mean duration from EVD to the first postoperative CT scan was 20 ± 4 h. EVD-related hematomas were detected after 81 procedures with a per-catheter risk of 8.1%. Mean hematoma volume was 1.2 ± 3.3 ml. Most were less than 1 ml (grade I, 79%, 64), 1 to 15 ml (grade II) in 20% (16) and a single clot larger than 15 ml (grade III, 1%) were detected. Clinically significant hemorrhage that resulted in catheter occlusion occurred in 1.7% (17) of procedures. Most catheters (62%, 625) were optimally placed, i.e., its tip being within the ipsilateral frontal horn or third ventricle. Three non-antibiotic-impregnated ventricular catheter designs were used with 55% (550) being the 2.2-mm Integra™ catheter, 14% (137) being the 2.8-mm Medtronic™ catheter, and 31% (315) being the 3.1-mm Codman™ catheter. Independent significant predictors for EVD-related hemorrhage were the preoperative prescription of aspirin (adjusted OR 1.94; 95% CI 1.10-3.44), catheter malposition (aOR 1.99; 95% CI 1.22-3.23), and use of the 2.8-mm Medtronic™ catheter (aOR 4.22; 95% CI 2.39-7.41). CONCLUSIONS: The per-catheter risk of hemorrhage was 8.1%, but the incidence of symptomatic hemorrhage was low. The only patient risk factor was aspirin intake. This is the first study to evaluate and establish an association between catheter malposition and catheter design with EVD-related hemorrhage.

Determining a cut-off residual tumor volume threshold for patients with newly diagnosed glioblastoma treated with temozolomide chemoradiotherapy: A multicenter cohort study.

Standard-of-care treatment of glioblastomas involves maximal safe resection and adjuvant temozolomide chemo-radiotherapy. Although extent of resection (EOR) is a well-known surgical predictor for overall survival most lesions cannot be completely resected. We hypothesize that in the event of incomplete resection, residual tumor volume (RTV) may be a more significant predictor than EOR. This was a multicenter retrospective review of 147 adult glioblastoma patients (mean age 53 years) that underwent standard treatment. Semiautomatic magnetic resonance imaging segmentation was performed for pre- and postoperative scans for volumetric analysis. Cox proportional hazards regression and Kaplan-Meier survival analyses were performed for prognostic factors including: age, Karnofsky performance score (KPS), O(6)-methylguanine methyltransferase (MGMT) promoter methylation status, EOR and RTV. EOR and RTV cut-off values for improved OS were determined and internally validated by receiver operator characteristic (ROC) analysis for 12-month overall survival. Half of the tumors had MGMT promoter methylation (77, 52%). The median tumor volume, EOR and RTV were 43.20 cc, 93.5%, and 3.80 cc respectively. Gross total resection was achieved in 52 patients (35%). Cox proportional hazards regression, ROC and maximum Youden index analyses for RTV and EOR showed that a cut-off value of <3.50 cc (HR 0.69; 95% CI 0.48-0.98) and ≥84% (HR 0.64; 95% CI 0.43-0.96) respectively conferred an overall survival advantage. Independent overall survival predictors were MGMT promoter methylation (adjusted HR 0.35; 95% CI 0.23-0.55) and a RTV of <3.50 cc (adjusted HR 0.53; 95% CI 0.29-0.95), but not EOR for incompletely resected glioblastomas.

A Comparative Analysis of the Usefulness of Survival Prediction Models for Patients with Glioblastoma in the Temozolomide Era: The Importance of Methylguanine Methyltransferase Promoter Methylation, Extent of Resection, and Subventricular Zone Location.

OBJECTIVE: Several survival prediction models for patients with glioblastoma have been proposed, but none is widely used. This study aims to identify the predictors of overall survival (OS) and to conduct an independent comparative analysis of 5 prediction models. METHODS: Multi-institutional data from 159 patients with newly diagnosed glioblastoma who received adjuvant temozolomide concomitant chemoradiotherapy (CCRT) were collected. OS was assessed by Cox proportional hazards regression and adjusted for known prognostic factors. An independent CCRT patient cohort was used to externally validate the 1) RTOG (Radiation Therapy Oncology Group) recursive partitioning analysis (RPA) model, 2) Yang RPA model, and 3) Wee RPA model, Chaichana model, and the RTOG nomogram model. The predictive accuracy for each model at 12-month survival was determined by concordance indices. Calibration plots were performed to ascertain model prediction precision. RESULTS: The median OS for patients who received CCRT was 19.0 months compared with 12.7 months for those who did not (P < 0.001). Independent predictors were: 1) subventricular zone II tumors (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0-2.5); 2) methylguanine methyltransferase promoter methylation (HR, 0.36; 95% CI, 0.2-0.6); and 3) extent of resection of >85% (HR, 0.59; 95% CI, 0.4-0.9). For 12-month OS prediction, the RTOG nomogram model was superior to the RPA models with a c-index of 0.70. Calibration plots for 12-month survival showed that none of the models was precise, but the RTOG nomogram performed relatively better. CONCLUSIONS: The RTOG nomogram best predicted 12-month OS. Methylguanine methyltransferase promoter methylation status, subventricular zone tumor location, and volumetric extent of resection should be considered when constructing prediction models.